The hypoxia-activated prodrug evofosfamide in combination with multiple regimens of radiotherapy

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Abstract

The promising treatment combination of ionizing radiation (IR) with a hypoxia-activated prodrug (HAP) is based on biological cooperation. Here we investigated the hypoxia-activated prodrug evofosfamide in combination with different treatment regimens of IR against lung A549- and head&neck UT-SCC-14-derived tumor xenografts. DNA damage-related endpoints and clonogenic cell survival of A549 and UT-SCC-14 carcinoma cells were probed under normoxia and hypoxia.

Evofosfamide (TH-302) induced DNA-damage and a dose-dependent antiproliferative response in A549 cells on cellular pretreatment under hypoxia, and supra-additively reduced clonogenic survival in combination with IR. Concomitant treatment of A549-derived tumor xenografts with evofosfamide and fractionated irradiation induced the strongest treatment response in comparison to the corresponding neoadjuvant and adjuvant regimens. Adjuvant evofosfamide was more potent than concomitant and neoadjuvant evofosfamide when combined with a single high dose of IR. Hypoxic UT-SCC-14 cells and tumor xenografts thereof were resistant to evofosfamide alone and in combination with IR, most probably due to reduced P450 oxidoreductase expression, which might act as major predictive determinant of sensitivity to HAPs.

In conclusion, evofosfamide with IR is a potent combined treatment modality against hypoxic tumors. However, the efficacy and the therapeutic outcome of this combined treatment modality is, as indicated here in preclinical tumor models, dependent on scheduling parameters and tumor type, which is most probably related to the status of respective HAP-activating oxidoreductases. Further biomarker development is necessary for the launch of successful clinical trials.

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Radiation-induced vascular damage in tumors: implications of vascular damage in ablative hypofractionated radiotherapy (SBRT and SRS).

David R J Griffin, Wook Song, Barrie H. Levitt … (2012)

We have reviewed the studies on radiation-induced vascular changes in human and experimental tumors reported in the last several decades. Although the reported results are inconsistent, they can be generalized as follows. In the human tumors treated with conventional fractionated radiotherapy, the morphological and functional status of the vasculature is preserved, if not improved, during the early part of a treatment course and then decreases toward the end of treatment. Irradiation of human tumor xenografts or rodent tumors with 5-10 Gy in a single dose causes relatively mild vascular damages, but increasing the radiation dose to higher than 10 Gy/fraction induces severe vascular damage resulting in reduced blood perfusion. Little is known about the vascular changes in human tumors treated with high-dose hypofractionated radiation such as stereotactic body radiotherapy (SBRT) or stereotactic radiosurgery (SRS). However, the results for experimental tumors strongly indicate that SBRT or SRS of human tumors with doses higher than about 10 Gy/fraction is likely to induce considerable vascular damages and thereby damages the intratumor microenvironment, leading to indirect tumor cell death. Vascular damage may play an important role in the response of human tumors to high-dose hypofractionated SBRT or SRS.

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Hypoxic modification of radiotherapy in squamous cell carcinoma of the head and neck--a systematic review and meta-analysis.

Jens Overgaard (2011)

The importance of tumour hypoxia for the outcome of radiotherapy has been under investigation for decades. Numerous clinical trials modifying the hypoxic radioresistance in squamous cell carcinoma of the head and neck (HNSCC) have been conducted, but most have been inconclusive, partly due to a small number of patients in the individual trial. The present meta-analysis was, therefore, performed utilising the results from all clinical trials addressing the specific question of hypoxic modification in HNSCC undergoing curative intended primary radiotherapy alone. A systematic review of published and unpublished data identified 4805 patients with HNSCC treated in 32 randomized clinical trials, applying, normobaric oxygen or carbogen breathing (5 trials); hyperbaric oxygen (HBO) (9 trials); hypoxic radiosensitizers (17 trials) and HBO and radiosensitizer (1 trial). The trials were analysed with regard to the following endpoints: loco-regional control (32 trials), disease specific survival (30 trials), overall survival (29 trials), distant metastases (12 trials) and complications to radiotherapy (23 trials). Overall hypoxic modification of radiotherapy in head and neck cancer did result in a significant improved therapeutic benefit. This was most dominantly observed when using the direct endpoint of loco-regional control with an odds ratio (OR) of 0.71, 95% cf.l. 0.63-0.80; p<0.001), but this was almost mirrored in the disease specific survival (OR: 0.73, 95% cf.l. 0.64-0.82; p<0.001), and to a lesser extent in the overall survival (OR: 0.87, 95% cf.l. 0.77-0.98; p=0.03). The risk of distant metastases was not significantly influenced although it appears to be less in the tumours treated with hypoxic modification (OR: 0.87, 95% cf.l. 0.69-1.09; p=0.22), whereas the radiation related late complications were not influenced by the overall use of hypoxic modifications (OR: 1.00, 95% cf.l. 0.82-1.23; p=0.96). The improvement in loco-regional control was found to be independent of the type of hypoxic modification. The trials have used different fractionation schedules, including large doses per fraction, which may result in relatively more hypoxia and greater benefit. However, analysis of HNSCC trials using conventional fractionation only, showed that the significant effect of hypoxic modification was maintained. The meta-analysis thus demonstrates that there is level 1a evidence in favour of adding hypoxic modification to radiotherapy of squamous cell carcinomas of the head and neck. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

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The hypoxic cell: a target for selective cancer therapy--eighteenth Bruce F. Cain Memorial Award lecture.

R. M. Brown (1999)

It has been appreciated for more than 50 years that very low levels of oxygenation, or hypoxia, both protect cells from killing by X-irradiation and are present in solid tumors but not in normal tissues. Until recently, however, there has been no definitive proof that hypoxia in human tumors contributes to radiotherapy treatment failure. We now know that hypoxia in solid tumors is not only a major problem for radiation therapy but also leads to resistance to most anticancer drugs and, importantly, appears to accelerate malignant progression and increase metastasis. To date, efforts to overcome the problem of hypoxia have had only limited success. However, the recent development of new drugs that are nontoxic until they are activated in the hypoxic cell opens a new era. The first of these new drugs to be tested clinically, tirapazamine, a drug that is highly toxic to hypoxic but not aerobic cells, has already demonstrated efficacy in selective potentiation of cisplatin in randomized Phase III trials with non-small cell lung cancer. The unique presence of hypoxic cells in human tumors provides an important target for selective cancer therapy.

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Author and article information

Journal

Journal ID (nlm-ta): Oncotarget

Journal ID (iso-abbrev): Oncotarget

Journal ID (publisher-id): Oncotarget

Journal ID (publisher-id): ImpactJ

Title: Oncotarget

Publisher: Impact Journals LLC

ISSN (Electronic): 1949-2553

Publication date Collection: 4 April 2017

Publication date (Electronic): 28 February 2017

Volume: 8

Issue: 14

Pages: 23702-23712

Affiliations

¹ Laboratory for Applied Radiobiology, Department of Radiation Oncology, University Hospital Zurich, Zurich, Switzerland

² Clinical Research Priority Program “Tumor Oxygenation”, Zurich, Switzerland

³ Department of Radiation Oncology, University Hospital Zurich, Zurich, Switzerland

Author notes

Correspondence to: Martin Pruschy, martin.pruschy@ 123456usz.ch

Article

Publisher ID: 15784

DOI: 10.18632/oncotarget.15784

PMC ID: 5410338

PubMed ID: 28423594

SO-VID: c95173d2-98b4-453c-976b-96bd26d17238

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This article is distributed under the terms of the Creative Commons Attribution License (CC-BY), which permits unrestricted use and redistribution provided that the original author and source are credited.

The hypoxia-activated prodrug evofosfamide in combination with multiple regimens of radiotherapy

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Most cited references 25

Radiation-induced vascular damage in tumors: implications of vascular damage in ablative hypofractionated radiotherapy (SBRT and SRS).

Hypoxic modification of radiotherapy in squamous cell carcinoma of the head and neck--a systematic review and meta-analysis.

The hypoxic cell: a target for selective cancer therapy--eighteenth Bruce F. Cain Memorial Award lecture.

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